The human spine is formed from twenty-six consecutive vertebrae. Each of these vertebrae is separated from any adjacent vertebra by an intervertebral disc that functions to absorb shock and prevent each vertebra from directly impacting upon another vertebra. At the center of each disc is a nucleus pulposus that contains proteoglycan. Around the nucleus pulposus is an outer ring called the annulus fibrosus. THE MERCK MANUAL OF DIAGNOSIS AND THERAPY 1478-1499 (Mark H. Beers and Robert Berkow eds., 17th ed. 1999).
Degenerative disc disease refers to any of the common degenerative conditions of the lower spine involving degeneration of the disc. Disc degeneration is often associated with the symptom of pain and may lead to inflammation and neuropathic pain, for example, spinal stenosis, spondylolisthesis, and retrolisthesis. THE MERCK MANUAL OF DIAGNOSIS AND THERAPY 475-478 (Mark H. Beers and Robert Berkow eds., 17th ed. 1999).
Disc degeneration associated with the aging process is generally associated with the loss of proteoglycan from the nucleus pulposus of the spinal discs and a reduction of the disc's ability to absorb shock between vertebrae. Although some affected patients may not exhibit symptoms, many affected patients suffer from chronic back and/or leg pain. Pain associated with disc degeneration may become debilitating and may greatly reduce a patient's quality of life. THE MERCK MANUAL OF DIAGNOSIS AND THERAPY 1488-1490 (Mark H. Beers and Robert Berkow eds., 17th ed. 1999).
While nonoperative treatments for disc degeneration exist, many patients, for example, those patients with severe symptoms, may not respond to nonoperative treatment. Conventional operative treatment generally involves spondylosyndesis (spinal fusion), which is highly invasive and is associated with certain risks to the patient. THE MERCK MANUAL OF DIAGNOSIS AND THERAPY 1488-1490 (Mark H. Beers and Robert Berkow eds., 17th ed. 1999).
While the biological mechanisms of degenerative disc disease are not well known, it is known that proteoglycans, which are abundant in the disc's nucleus, decline in content with age, are believed to be an important factor in the pathogenesis of the disease. Degenerated and herniated discs are known to produce increased amounts of proteins such as nitric oxide (NO), cytokines, such as interleukin-1 (IL-1 and IL-1β), interleukin-6 (IL-6) and TNF-alpha, prostaglandin E2 (PGE2) and matrix metalloproteases (MMP). These proteins play a regulatory role in the interactions between the biochemical agents produced by degenerated discs. Le Maitre, C. L., et al. (2004) “Localization of degradative enzymes and their inhibitors in the degenerate human invertebral disc,” J. Pathol 204:47-54.
Potential therapeutic molecules can be classified as inflammatory mediators, anticatabolics, mitogens, and chondrogenic morphogens. Inflammatory mediators can include TNF-alpha agonists or antagonists such as infliximab (remicade) and etanercept; TNF-alpha stimulated gene-6 (TSG-6); IL-1 receptor antagonists (IL-1R); regulators of IL-6, IL-8, and IL-10; NF-κB inhibitors; MCP-1 inhibitors, and selective COX-2 inhibitors such as rofecoxib and nimesulide. Anticatabolic therapeutics include tissue inhibitors of matrix metalloproteases (TIMPs), such as TIMP-1 and -3, and the biphosphonates clodronate and pamidronate. Mitogens include insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and hyaluronan. Chodrogenic morphogens include transforming growth factor-beta (TGF-beta) and growth and differentiation factor-5 (GDF-5). Other possible enzymes for inhibition are those with a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) and aggrecanase. Roberts, S., et al. (2000) “Matrix Metalloproteinases and Aggrecanase,” SPINE 25(23):3005-3013. Chemically modified tetracyclines have been shown to inhibit both production and activity of various members of the MMP family of enzymes. Fingleton, B. (2003) “CMT-3 CollaGenex,” Current Opinion in Investigational Drugs 4(12):1460-1467; U.S. Pat. No. 6,946,453, issued Sep. 20, 2005 (Ashley, et al.); U.S. Pat. No. 6,894,036, issued May 17, 2005 (Ashley, et al.); U.S. Pat. No. 6,638,922, issued Oct. 28, 2003 (Ashley, et al.); U.S. Pat. No. 5,773,430, issued Jun. 30, 1998 (Simon, et al.).